Desethylamiodarone—A metabolite of amiodarone—Induces apoptosis on T24 human bladder cancer cells via multiple pathways

Abstract

Bladder cancer (BC) is a common malignancy of the urinary tract that has a higher frequency in men than in women. Cytostatic resistance and metastasis formation are significant risk factors in BC therapy; therefore, there is great interest in overcoming drug resistance and in initiating research for novel chemotherapeutic approaches. Here, we suggest that desethylamiodarone (DEA)–a metabolite of amiodarone—may have cytostatic potential. DEA activates the collapse of mitochondrial membrane potential (detected by JC-1 fluorescence), and induces cell death in T24 human transitional-cell bladder carcinoma cell line at physiologically achievable concentrations. DEA induces cell cycle arrest in the G0/G1 phase, which may contribute to the inhibition of cell proliferation, and shifts the Bax/Bcl-2 ratio to initiate apoptosis, induce AIF nuclear translocation, and activate PARP-1 cleavage and caspase-3 activation. The major cytoprotective kinases—ERK and Akt—are inhibited by DEA, which may contribute to its cell death-inducing effects. DEA also inhibits the expression of B-cell-specific Moloney murine leukemia virus integration site 1 (BMI1) and reduces colony formation of T24 bladder carcinoma cells, indicating its possible inhibitory effect on metastatic potential. These data show that DEA is a novel anti-cancer candidate of multiple cell death-inducing effects and metastatic potential. Our findings recommend further evaluation of its effects in clinical studies.

Amiodarone’s major metabolite, desethylamiodarone inhibits proliferation of B16-F10 melanoma cells and limits lung metastasis formation in an in vivo experimental model

“…Previously, we demonstrated that DEA significantly inhibited the proliferation and viability of T24 human transitional cell bladder carcinoma and HeLa human cervical cancer cell lines [ 12 , 13 ]. It mitigated colony formation in vitro , as well as it induced apoptosis and G0/G1 phase cell cycle arrest in a dose-dependent manner [ 12 , 13 ], exactly as it did in the present study in mouse B16-F10 melanoma cells (Figs 1 – 4 ). In vitro antiproliferative and apoptosis-promoting properties of a drug represent a rather poor translational value for its potentiality in human cancer therapy.…”

“…These side effects manifest in cardial, ocular, pulmonary, hepatic, dermatologic, hematological, psychiatric, thyroid and neuromuscular adverse reactions, and chronic AM treatment even can cause epididymitis and syndrome of inappropriate antidiuretic hormone secretion [11]. Based on its tissue accumulation properties and toxic effects, we proposed its potentiality in cancer therapy [12,13]. In this study, we investigated DEA's therapeutic potentiality in metastatic melanoma since new effective and safe treatments for this type of cancer are urgently needed.…”

Involvement of Mitochondrial Mechanisms in the Cytostatic Effect of Desethylamiodarone in B16F10 Melanoma Cells

“…In complete agreement with our previous results obtained in isolated liver and heart mitochondria [ 18 ], 10 µM of DEA induced a CsA-independent mPT ( Figure 5 ). This likely contributes to DEA’s cytotoxicity in cultured bladder carcinoma, cervical carcinoma, and melanoma cells [ 15 , 16 , 17 ]. Furthermore, DEA definitely compromised IMM integrity, as calcein fluorescence was not quenched in the absence of DEA or Ca 2+ stimulation (data not shown).…”

NACC1, as a Target of MicroRNA-331-3p, Regulates Cell Proliferation in Urothelial Carcinoma Cells

“…Conventional anticancer drug for UC therapy, such as vinblastine, doxorubicin, and cisplatin act during DNA synthesis and/or various phases of the cell cycle checkpoint, and produce anticancer effects [ 19 ]. There are several reports about anticancer drugs and biological compounds, such as desethylamiodarone [ 20 ], reversine [ 21 ], isoquercitrin [ 22 ], trichostatin A [ 23 ], and miconazole [ 24 ], for chemotherapy of UC. Moreover, the histone deacetylase (HDAC) inhibitor valproic acid (VPA), anticancer agent amygdalin and chalcone, which is a precursor compound for flavonoid synthesis in plants, induced cell growth inhibition via cell cycle arrest at G0/G1 or G2/M phase in UC [ 25 , 26 , 27 ].…”